DESCRIPTION: Drug candidates that disrupt the NEMO/IKK signaling complex for the treatment of cancer Project Summary/Abstract Protein-protein interactions represent the largest untapped opportunity for therapeutic development, but the field has languished due to lack of efficient lead finding technologies. To address these shortcomings, Carmot is developing an innovative drug discovery technology called Chemotype Evolution. Chemotype Evolution provides access to novel and target-relevant chemical diversity with an efficiency that is unprecedented with other technologies. Importantly, through iterative applications of Chemotype Evolution, a starting peptide can be evolved into smaller and more drug-like molecules. Carmot has successfully applied this approach to target the NEMO/IKK protein-protein interaction, a key mediator of NF-kB activation. This Phase II proposal will advance the promising hits identified during Phase I to support Carmot's long-term objective to develop drugs that inhibit cancer cell survival and inflammatory signaling in the tumor environment by inhibiting NF-kB activation. The NF-kB pathway is critical for the progression of leukemia and lymphoma and is directly activated by several cancer-associated mutations. NF-kB is also a key signaling node in the communication between tumors and the inflammatory microenvironment by promoting inflammation, cell survival, cell proliferation, angiogenesis, and tissue remodeling. However, despite intensive efforts, viable drug-leads that specifically target NF-kB activation have not been identified. The protein-protein interaction between NF-kB Essential Modulator (NEMO) and IkB Kinase (IKK), referred to as NEMO/IKK, has emerged as a promising target for inhibiting NF-kB activation. The technical objective of this Phase II proposal is to advance NEMO/IKK inhibitors identified in Phase I toward proof-of-concept in animal models. Specifically, Carmot will use Chemotype Evolution and medicinal chemistry to improve potency, cell activity, and pharmaceutical properties (aim 1). Next, Carmot will test compounds as single agents and in combination with approved chemotherapeutics in cell-based models of lymphoma and evaluate markers of drug response (aim 2). Finally, select compounds will be tested in animal models of lymphoma with the goal of identifying drug candidates for further pre-clinical development (aim 3). Two products will emerge from the Phase II research. First, this proposal will validate an innovative technology for targeting protein-protein interactions by progressively converting a peptide ligand into a smaller more drug-like molecule, thus addressing a major technological gap in pharmaceutical discovery. Second, the identified molecules will serve as new drug candidates for treatment of leukemias, lymphomas, and solid tumors.